Cancer Chemotherapy and Pharmacology

, Volume 81, Issue 6, pp 1043–1050 | Cite as

Phase II study of cisplatin/pemetrexed combined with bevacizumab followed by pemetrexed/bevacizumab maintenance therapy in patients with EGFR-wild advanced non-squamous non-small cell lung cancer

  • Toshirou Fukushima
  • Yuuki Wakatsuki
  • Takashi Kobayashi
  • Kei Sonehara
  • Kazunari Tateishi
  • Manabu Yamamoto
  • Takeshi Masubuchi
  • Fumiaki Yoshiike
  • Kazuya Hirai
  • Tsutomu Hachiya
  • Tomonobu Koizumi
Original Article



This phase II study was performed to evaluate the efficacy and safety of cisplatin/pemetrexed combined with 15 mg/kg of bevacizumab followed by pemetrexed/bevacizumab maintenance therapy as first-line chemotherapy in advanced non-squamous non-small cell lung cancer (NSCLC) limited to epidermal growth factor receptor (EGFR)-wild type.

Patients and methods

Fifty patients with advanced or metastatic EGFR-wild type NSCLC aged < 75 years old were enrolled in the study. The patients were treated with four cycles of cisplatin (75 mg/m2, day 1), pemetrexed (500 mg/m2, days 1), and bevacizumab (15 mg/kg, day 1), every 3 weeks, followed by pemetrexed plus bevacizumab maintenance until progression for achieving a response over stable disease after induction chemotherapy.


Partial response and stable disease were observed in 35 (objective response rate: 70, 95% CI: 55.4–82.1%) and 9 patients, respectively, and 39 (78%) patients received pemetrexed plus bevacizumab maintenance therapy. Median progression-free survival and overall survival periods were 12.0 months (95% CI: 7.5–16.5 months) and 31.0 months (95% CI: 22.2–39.8 months), respectively. Grade 3 adverse events included neutropenia (14%), nausea (10%), anorexia (18%), and hypertension (8%). Coagulation disorder was observed in one patient, but all of these events were reversible and resulted in no treatment-related deaths.


The combination of cisplatin/pemetrexed/bevacizumab followed by pemetrexed/bevacizumab maintenance therapy exhibited favorable efficacy and manageable toxicity profiles in patients with EGFR-wild type non-squamous NSCLC (UMIN-CTR number: UMIN000003645).


Anti-VEGF agent EGFR-wild type Non-small cell lung cancer Continuation maintenance 



The authors would like to acknowledge the following for their participation in the present study. The investigators and institutions were as follows: Dr. Hiroshi Kuraishi, Nagano Red Cross Hospital; Dr. Tetsuo Kimura and Nobutoshi Morozumi, Saku Central Hospital Advanced Care Center; Dr. Toshihiko Agatsuma, Shinshu Ueda Medical Center; Dr. Akio Morikawa, Showa Inan General Hospital; Dr. Kouji Sakaguchi, Nagano Prefectural Shinshu Medical Center; Dr. Hozumi Tanaka, Iida Hospital; and the Staff of the First Department of Internal Medicine, Shinshu University School of Medicine.

Compliance with ethical standards

Conflict of interest

Dr Koizumi received research grants from AstraZeneca, Ono Pharmaceutical CO., LTD, Chugai Pharmaceutical CO., LTD, outsides the submitted work. The remaining authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Toshirou Fukushima
    • 1
  • Yuuki Wakatsuki
    • 1
  • Takashi Kobayashi
    • 1
  • Kei Sonehara
    • 2
  • Kazunari Tateishi
    • 2
  • Manabu Yamamoto
    • 3
  • Takeshi Masubuchi
    • 3
  • Fumiaki Yoshiike
    • 4
  • Kazuya Hirai
    • 4
  • Tsutomu Hachiya
    • 5
  • Tomonobu Koizumi
    • 1
  1. 1.Department of Comprehensive Cancer TherapyShinshu University School of MedicineNaganoJapan
  2. 2.First Department of Internal MedicineShinshu University School of MedicineMatsumotoJapan
  3. 3.Department of Pulmonary DiseaseNagano Red Cross HospitalNaganoJapan
  4. 4.Department of Pulmonary DiseaseNagano Municipal HospitalNaganoJapan
  5. 5.Department of Pulmonary DiseaseSuwa Red Cross HospitalSuwaJapan

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